Conditional Deletion of MSX Homeobox Genes in the Uterus Inhibits Blastocyst Implantation by Altering Uterine Receptivity

Abstract

An effective bidirectional communication between an implantation-competent blastocyst and the receptive uterus is a prerequisite for mammalian reproduction. The blastocyst will implant only when this molecular cross-talk is established. Here we show that the muscle segment homeobox gene (Msh) family members Msx1 and Msx2, which are two highly conserved genes critical for epithelial-mesenchymal interactions during development, also play crucial roles in embryo implantation. Loss of Msx1/Msx2 expression correlates with altered uterine luminal epithelial cell polarity and affects E-cadherin/β-catenin complex formation through the control of Wnt5a expression. Application of Wnt5a in vitro compromised blastocyst invasion and trophoblast outgrowth on cultured uterine epithelial cells. The finding that Msx1/Msx2 genes are critical for conferring uterine receptivity and readiness to implantation could have clinical significance, because compromised uterine receptivity is a major cause of pregnancy failure in IVF programs.

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

“…48,49 This timely remodeling of junction complexes under the control of ovarian steroid hormones represents a decreased epithelial apicalbasal polarity during uterine receptivity establishment. 9,11,45 In fact, previous studies have demonstrated a lack of transition of the luminal epithelium from a high to a less apical-basal polar state in the absence of uterine Msx1 and 2 genes hampers blastocyst implantation. 9 As a small GTPase, Rac1 has been found crucial in regulating cell shape and epithelial polarity.…”

“…9,11,45 In fact, previous studies have demonstrated a lack of transition of the luminal epithelium from a high to a less apical-basal polar state in the absence of uterine Msx1 and 2 genes hampers blastocyst implantation. 9 As a small GTPase, Rac1 has been found crucial in regulating cell shape and epithelial polarity. For example, Rac1 mutant lens placode cells are shorter and more apically restricted than the control cells.…”

“…For example, on day 4 morning in mice, luminal epithelial cells cease proliferation under the dominance of increasing levels of ovarian progesterone and preimplantation estrogen. Meanwhile, the epithelial cells undergo differentiation, accompanied with a dynamic junction complex remodeling and membrane maturation, leading to a decrease of epithelial polarity approaching implantation and a cell-shape transition from columnar to cubical configuration, 9 thus gradually achieving the capacity for blastocyst attachment on day 4 evening. 10 Therefore, a timely regulated epithelial membrane maturation and precisely maintained epithelial integrity is critical for embryo implantation.…”

Uterine receptivity and embryo–uterine interactions in embryo implantation: lessons from mice

“…Recently, MSX homeobox genes are reported to be essential transcriptional regulators which morphologically modulate luminal epithelium and control normal implantation in mice [17]. Uterine deletion of both Msx1 and Msx2 completely inhibits blastocyst implantation [17].…”

“…Uterine deletion of both Msx1 and Msx2 completely inhibits blastocyst implantation [17]. LIF reduces uterine Msx1 expression and deficiency of Msx1/2 reduces LIF expression [17].…”